In a small phase II study, MS patients with optic neuritis who were on the drug had better preservation of retinal thickness and macular volume than those on placebo, although visual outcomes were similar.

And in a suite of early-stage clinical studies, orally active ion channel modulators relieved muscle cramps in healthy volunteers, potentially leading to treatments for multiple sclerosis spasticity, cervical dystonia, and a host of other conditions.

Some early studies have shown that the partial blockade of voltage-gated sodium channels may be neuroprotective. Phenytoin being a sodium channel blocker, as well as a drug with an established safety record, Kapoor and colleagues randomized 86 MS patients with acute optic neuritis to the agent at 4 mg/kg/day or to placebo for 3 months.

The primary outcome was RNFL thickness in the affected eye at 6 months.

Ultimately, five patients were lost to follow-up, so 81 were assessed for the intention-to-treat comparison.

Kapoor and colleagues found that patients in the phenytoin group had 30% less damage to the nerve fiber layer compared with placebo, with RNFL thickness that was 7.15 mcm higher in the drug group (P=0.02).

The volume of the macula was 34% higher in those on phenytoin compared with placebo, with a 0.20 mm3 greater volume among patients in the active group (P=0.005).

However, there were no differences in visual outcomes between the two groups.

Still, they concluded that phenytoin protects the RNFL and the macula from neurodegeneration in acute optic neuritis, raising the possibility that blockage of voltage-gated sodium channels may be neuroprotective in relapses of MS in general.

Kapoor said in a statement that if the findings are confirmed in larger studies, it may lead to a treatment to prevent nerve damage and blindness in MS.

Shlomo Shinnar, MD, PhD, of Montefiore Medical Center in New York, who was not involved in the study, was not immediately convinced of the utility of the drug in this condition.

"Over the years, phenytoin has been reported to have a wide range of effects in a variety of disorders. Most have not been confirmed," Shinnar said in an email to MedPage Today.

He agreed with Kapoor that the result needs confirmation in a more definitive study. In addition, he noted that the lack of a difference in actual vision means that the clinical significance of the finding remains unclear.

"As we continue to search for disease modifying/neuroprotective agents, our enthusiasm for preliminary findings is tempered by a long history of promising agents that subsequently more definitive trials did not find to be effective," Shinnar said.

The ion channel modulators were assessed in 37 volunteers enrolled in three separate placebo-controlled crossover trials.

The treatment "significantly reduc[ed] cramp intensity by threefold (P<0.001) and demonstrat[ed] an effect within minutes lasting up to 6-8 hours when compared to untreated subjects." These findings were also reported at the AAN's annual meeting.

The researchers explained that cramping appears to result from repetitive firing of so-called alpha neurons with resulting hyperexcitability in motor circuits. The physiology of these neuronal connections involves ion movement into and out of cells, suggesting that ion channel modulators may provide opportunities to intervene in these processes.

MacKinnon won the 2003 Nobel Prize in chemistry for his structural and mechanistic studies of ion channels (shared with Peter Agre, credited with the discovery of water channels).

The clinical studies used "a proprietary product containing TRP activators." Flex Pharma elsewhere describes the product as containing ginger and cinnamon extracts and capsicum. These plant-based agents are FDA-listed as "generally recognized as safe," according to Flex. Preclinical tests had shown that the compounds, singly and in combination, increased intracellular calcium levels in human dorsal root ganglia tissue.

The hypothesized mechanism of action in cramping, according to the firm, is that activating TRP channels in sensory neurons in the GI tract will, in turn, send signals to the spinal cord that then create "an inhibitory effect ... on alpha motor neurons throughout the body, thereby reducing neuron excitation and muscle cramps."

Flex, which became a public company a few weeks ago in an $86-million offering, is targeting numerous conditions for the treatment. Besides MS spasticity and cervical dystonia, these also include nocturnal cramps afflicting older adults and cramping resulting from muscle exertion.

In materials for potential investors, Flex estimated that some 4 million people older than 65 suffer from cramps every night.

The firm intends to conduct a proof-of-concept clinical study later this year in that indication.

Its plans also call for the TRP activators to be formulated as a dietary supplement -- and thus beyond the FDA's drug regulation -- for preventing exercise-induced cramps. A commercial launch could come in the first half of 2016, the firm said.

For treatment of medical conditions such as spasticity and dystonia, Flex will pursue formal FDA approvals. The firm estimates that at least 200,000 Americans with MS experience spasticity. Another 150,000 suffer spasticity from spinal cord injury, and some 90,000 have cervical dystonia.

Kapoor and Shinnar disclosed no financial relationships with industry.

The ion channel modulator study was supported by Flex and the authors received financial support from the company.

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